Dermal drug formulations may represent the oldest drug dosage form in human history. It is highly probable that even ancient people used resins and animal fats to treat damage to the skin resulting from injuries and burns. The use of such dermal formulations for local effect remained largely unchanged until the middle of this century. The concept of administering drugs through the skin to achieve a local or systemic effect was first seriously advocated by Dr. Alejandro Zaffaroni in the early 1970's. Since that time extensive research has been undertaken in this field.
The transdermal route of drug administration offers a number of advantages over the more conventional routes of drug administration. For instance, a drug may be delivered to targeted tissues from adjacent skin areas. The transdermal route of drug administration also allows for a gradual, controlled release of drug into the systemic circulation. Since many drugs are poorly absorbed or delivered through the traditional routes of administration, the transdermal route provides an effective method of achieving improved bioavailability for those drugs. The transdermal route of drug administration is also advantageous since the administration of dermally administered drugs may be easily stopped should an undesirable side effect occur during therapy.
In spite of the foregoing advantages, transdermal formulations are limited. They cannot be used with most polar drugs since they tend to penetrate the skin too slowly. This characteristic is particularly crucial since most drugs are of a polar character. In addition, many drugs elicit a reaction and/or irritation at the site of topical application.
Two methods are known for improving the rate of penetration of polar drugs across the skin. The first method is to make a better formulation of the drug to increase its thermodynamic activity. The thermodynamic activity of a drug in a dermal formulation is dependent on the concentration of the drug and the choice of the vehicle. According to the laws of thermodynamics, the maximum activity of the drug is usually fixed by that of the pure state, i.e., the drug crystal. The second method involves the use of compounds or penetration enhancers to increase the permeability of the barrier membrane. The latter method is generally more practical because of its convenience and effectiveness.
Thus, in the last two decades, a wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. The classically recognized strong enhancers tend to be proton accepting solvents, e.g., dimethyl sulfoxide (DMSO) and dimethyl acetamide (DMA). Recently, 2-pyrrolidone, N,N-diethyl-m-toluamide (Deet), 1-dodecylazacycloheptane-2-one (Azone, a registered trademark of Nelson Research), N,N-dimethylformamide, N-methyl-2-pyrrolidone and calcium thioglycolate have been reported as effective enhancers. The structures of these compounds are set forth in Table I.
TABLE I ______________________________________ Dimethyl Sulfoxide (DMSO) ##STR2## N,N-Dimethyl Acetamide (DMA) ##STR3## N,N-Diethyl-m-Toluamide (Deet) ##STR4## 1-Dodecylazacycloheptane-2-One (Azone or laurocapram) ##STR5## 2-Pyrrolidone- 5-Carboxylic Acid ##STR6## 2-Pyrrolidone ##STR7## N,N-Dimethylformamide ##STR8## N-methyl-2-pyrrolidone ##STR9## calcium thioglycolate CaCH.sub.2 COOS.3H.sub.2 O ______________________________________
See, for example, the review article by Kenneth A. Walters entitled "Percutaneous absorption and transdermal therapy," Pharmaceutical Technology, March 1986, pp. 30-46, which discusses the use of surfactants and penetration enhancers to improve skin transport and their possible mechanisms of action.
Several problems have been associated with these prior art dermal enhancers. They cannot be applied to most polar drugs because they tend to penetrate the skin too slowly. And many of these prior art dermal enhancers produce reactions and/or irritation at the site of application.
In the search for new dermal penetration enhancers, Rinta Iubuki, in his Ph.D. Thesis in 1985 at the University of Kansas entitled "Use of Snake Skin as a Model Membrane for Percutaneous Absorption Studies," investigated the use of six compounds for transdermal penetration enhancement of indomethacin in a dosage form of a petrolatum ointment. The compounds disclosed in his thesis are presented below: ##STR10##
The primary problem with these compounds is their toxicity. Obviously, if a compound when used as a dermal enhancer is either toxic, irritating or allergic, then that compound is unsuitable for application to the human body. DMSO and DMA are also not clinically acceptable for those reasons. Deet and Azone have lower reported toxicities yet their toxicity is high enough such that they are not widely used.
In developing effective dermal enhancers, it would be advantageous to evaluate the potential enhancers by in vivo determination of the rate of human skin penetration of a drug administered along with the enhancer. The amount of drug could be measured in the host's circulation or in the target tissue. Unfortunately, due to the risks involved and the cost of such an evaluation, human in vivo determination is not practical. Thus, researchers have used a variety of mammals for in vivo study. Typical mammals include mice, rats, rabbits, pigs and dogs. However, significant differences have been found in the pattern of drug penetration among these mammals and humans. Although the reason for this species variation has not been well-established, the difference in the density of hair follicles is considered to be a factor.
Thus, the disadvantage of in vivo methods has encouraged wide use of various in vitro methods. Copending application U.S. Ser. No. 901,732, filed Aug. 29, 1986, now U.S. Pat. No. 4,771,044, incorporated by reference herein, discloses a novel method for in vitro determination of transdermal absorption. The method involves the use of shed snake skin.
In spite of the numerous attempts in the art to prepare a method for enhancing the absorption of drugs, especially polar drugs, through the skin, there still exists a clear and present need in the art for a method to enhance the absorption of drugs through the skin. This need has been addressed by co-pending application U.S. Ser. No. 096,092, filed Sept. 11, 1987, now U.S. Pat. No. 4,845,233, which describes a novel group of cyclic urea compounds which enhance the absorption of active substances through the skin while avoiding the significant pharmacological activities and toxicities of the prior art enhancers. The soft penetration enhancers of Ser. No. 096,092, now U.S. Pat. No. 4,845,233, have the formula ##STR11## wherein R, R.sub.1 and R.sub.2 are independently selected from hydrogen; hydroxy; fluorine; bromine; chlorine; C.sub.1 -C.sub.20 alkyl; C.sub.2 -C.sub.20 alkenyl; C.sub.2 -C.sub.20 alkynyl; C.sub.3 -C.sub.10 cycloalkyl; C.sub.2 -C.sub.20 (monohydroxy or polyhydroxy)alkyl; C.sub.1 -C.sub.20 (monohalo or polyhalo)alkyl; carboxy; C.sub.1 -C.sub.20 alkylcarboxy; C.sub.1 -C.sub.20 alkenylcarboxy; C.sub.1 -C.sub.20 carboxyalkyl; C.sub.1 -C.sub.20 alkanoyl; C.sub.1 -C.sub.20 alkanoyloxy; C.sub.1 -C.sub.20 alkoxycarbonyl; carbamoyl; carbamyl; C.sub.1 -C.sub.20 alkylcarbamyl; sulfo; C.sub.1 -C.sub.20 alkylsulfonyl; C.sub.1 -C.sub.20 alkylsulfinyl; C.sub.1 -C.sub.20 alkylsulfoxide; C.sub.1 -C.sub.20 alkylsulfone; thio; C.sub.1 -C.sub.20 alkylthio; amino; nitro; C.sub.1 -C.sub.20 alkylamino; C.sub.1 -C.sub.20 aminoalkyl; substituted or unsubstituted phenyl or benzyl, the substituents being selected from hydroxy, fluorine, bromine, chlorine, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 (monohydroxy or polyhydroxy)alkyl; X is methylene or oxygen and n is 0 to 20.
Improvement of transdermal drug delivery has thus been a focus of pharmaceutical research for many years. However, the stratum corneum presents a formidable barrier to percutaneous drug absorption. This barrier function is believed to be due to the ordered matrix of intercellular lipids and to the low water content in the stratum corneum. Since human gingivae also have stratum corneum, the problems besetting development of gingival formulations are much the same. There is clearly a need for additional novel compounds which enhance the absorption of active substances through the skin and mucous membranes such as the gingivae, but which are designed to have greatly reduced toxicity.